Background
Retrospective, registry-based EBMT comparative study. 2,654 patients with AML or MDS undergoing allo-HCT: 574 received treosulfan/fludarabine (Treo/Flu) conditioning, vs 1,183 standard MAC (busulfan/cyclophosphamide or TBI-based) and 897 RIC. Treosulfan is a bifunctional alkylating prodrug with myeloablative potency but lower organ toxicity than busulfan — proposed as an intermediate conditioning intensity between MAC and RIC.
Interventions and follow up
Design: Registry comparison of three conditioning regimens prior to allo-HCT
Treo/Flu (n=574): Treosulfan + fludarabine
MAC (n=1,183): Busulfan-cyclophosphamide or TBI-based
RIC (n=897): Fludarabine-busulfan or fludarabine-melphalan
Primary endpoint: GVHD-free, relapse-free survival (GRFS)
Median follow up: 36 months
Treo/Flu (n=574): Treosulfan + fludarabine
MAC (n=1,183): Busulfan-cyclophosphamide or TBI-based
RIC (n=897): Fludarabine-busulfan or fludarabine-melphalan
Primary endpoint: GVHD-free, relapse-free survival (GRFS)
Median follow up: 36 months
Results
3-year GRFS: 38.4% (Treo/Flu) vs 29.2% (MAC) vs 31.8% (RIC)
3-year NRM: 17.5% vs 27.3% vs 22.1% — lowest with Treo/Flu
3-year relapse: 32.1% vs 25.0% vs 35.6% — intermediate for Treo/Flu
3-year OS: 56.9% vs 49.5% vs 51.2%
3-year NRM: 17.5% vs 27.3% vs 22.1% — lowest with Treo/Flu
3-year relapse: 32.1% vs 25.0% vs 35.6% — intermediate for Treo/Flu
3-year OS: 56.9% vs 49.5% vs 51.2%
Adverse events
Mucosal/GI: Mucositis lower with Treo/Flu vs MAC (grade ≥3 ~15% vs ~30%); less diarrhea vs MAC
Hepatic: Hepatic VOD lower with Treo/Flu vs busulfan-MAC
Neurologic/engraftment: Minimal CNS penetration (lower neurotoxicity than busulfan); reliable engraftment comparable to MAC
Hepatic: Hepatic VOD lower with Treo/Flu vs busulfan-MAC
Neurologic/engraftment: Minimal CNS penetration (lower neurotoxicity than busulfan); reliable engraftment comparable to MAC
Conclusions
Treosulfan/fludarabine demonstrated GRFS and OS numerically superior to both MAC and RIC in this large EBMT registry analysis, with lower NRM than MAC and lower relapse than RIC — positioning it as an intermediate-intensity conditioning with a favorable safety profile.
Key Limitations
Retrospective registry design with non-randomized treatment allocation — selection bias and confounding by indication are inherent (conditioning chosen by physician/center). Patient, disease, and center heterogeneity across arms limits causal inference. No central review of toxicity or response; some endpoints estimated rather than directly compared. Findings are hypothesis-generating and require confirmation in randomized trials.
Clinical Context
Treosulfan/fludarabine is an established intermediate-intensity conditioning platform in AML/MDS allo-HCT. The pivotal randomized phase III (MC-FludT.14/L) showed superior outcomes vs reduced-intensity busulfan/fludarabine, supporting EMA approval (2019) and FDA approval (January 2025) of treosulfan with fludarabine as a preparative regimen for allo-HCT in adult and pediatric AML/MDS. This EBMT registry analysis provides supportive real-world comparative data.